Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review

Department of Psychiatry, Faculty of Medicine, University of Montreal, Fernand-Seguin Research Center, Louis-H Lafontaine Hospital, Montreal, Quebec, Canada.
Biological psychiatry (Impact Factor: 10.26). 05/2008; 63(8):801-8. DOI: 10.1016/j.biopsych.2007.09.024
Source: PubMed


Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence.
Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers.
Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines.
These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

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    • "Cytokines are small signaling molecules that regulate the cells of the immune system, which also constitute part of the common pathways for genetic and environmental factors contributing to the development of schizophrenia (Watanabe et al., 2010). The increased levels of inflammatory cytokines, such as IL-12, IFN-g, and TNF-a, have been reported in peripheral blood from schizophrenia patients by recent meta-analyses (Miller et al., 2011; Potvin et al., 2008). In central nervous system (CNS), abnormal expression of certain cytokines such as IL-2 and IL-1 receptor antagonist, has also been documented (McAllister et al., 1995; Toyooka et al., 2003). "
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    ABSTRACT: The pathophysiology of cognitive deficits in schizophrenia may involve the neuroinflammation mediated by cytokines. This study examined the IL-18 levels, the cognitive function, and their association in schizophrenia. We recruited 70 chronic patients and 75 normal controls and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and IL-18 levels. Positive and Negative Syndrome Scale (PANSS) was assessed in chronic patients. IL-18 levels were increased in chronic patients as compared to normal controls (p<0.01). RBANS total score and the subscales of immediate memory and delayed memory were lower in patients than controls (all p<0.001). In patients, IL-18 levels were positively associated with RBANS total score and the subscales of immediate and delayed memory (all p<0.05). Multiple regression analysis further confirmed that IL-18 was an independent contributor to RBANS total score and the aforementioned two indexes (all p<0.05). Our data demonstrate that immune responses may play an important role in cognitive deficits in schizophrenia and the abnormal levels of IL-18 reflecting the disturbed balance of proinflammatory and anti-inflammatory mechanisms may be relevant to cognitive deficits of this disorder.
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    • "However, data published so far have been inconsistent , which may be the result of differences in assay methodology, sample size, sample handling, diagnostic criteria, and comparison groups (Yao and van Kammen, 2004). Nevertheless, in a meta-analysis of 62 cross-sectional studies involving 2298 SZ patients and 1858 healthy volunteers , Potvin et al. (2008) concluded that SZ patients have increased levels of in vivo IL-1 receptor antagonist, soluble IL-2 receptor, and IL- 6, and decreased levels of in vitro IL-2, establishing an inflammatory syndrome in SZ. More recently, Miller et al. (2011) also concluded that there are significant increases for IL-6, IL-12, TNF-α, IL-1β, IL-8, TGF-β, IL-1 RA, IFN-γ, and sIL-2R, whereas IL-10 is significantly reduced in patients with first-episode psychosis. "
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    • "Although there is a general consensus that the dopaminergic neurotransmission is involved in the pathophysiology of schizophrenia, the role of the inflammatory process in the pathogenesis of schizophrenia has been discussed since almost a century (Dameshek 1930). A growing body of evidence indicates increased levels of pro-inflammatory cytokines in schizophrenia patients (Potvin et al. 2008; Drexhage et al. 2010; Miller et al. 2011). Among them, IL-6, IL-10 and TNFa (Cazullo et al. 1998; Kunz et al. 2011; Miller et al. 2011) gained special research attention. "
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    ABSTRACT: Many psychiatric disorders, like schizophrenia, affective disorders, addictions and different forms of dementia are associated with sleep disturbances. In the etiology and course of those diseases inflammatory processes are regarded to be an increasingly important factor. They are also a frequently discussed element of the pathology of sleep. In this literature review reports on correlations between poor sleep and inflammatory responses in various psychiatric conditions are discussed. The link between schizophrenia, affective disorders and inflammatory cytokines is a complex phenomenon, which has been already confirmed in a number of studies. However, the presence of sleep deficits in those conditions, being a common symptom of depression and psychoses, can be an additional factor having a considerable impact on the immunological processes in mental illnesses. In the analyzed data, a number of studies are presented describing the role of inflammatory markers in sleep disturbances and psychopathological symptoms of affective, psychotic, neurogenerative and other disorders. Also attention is drawn to possible implications for their treatment. Efforts to use, e.g., anti-inflammatory agents in psychiatry in the context of their impact on sleep are reported. The aspect of inflammatory markers in the role of sleep deprivation as the treatment method in major depressive disorder is also discussed. A general conclusion is drawn that the improvement of sleep quality plays a crucial role in the care for psychiatric patients.
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